Effect of Age on Response to Amblyopia Treatment in Children FREE

Evidence that amblyopia treatment is effective in some older children^1- 2 raises the longstanding question of whether or not there is a relationship between age and magnitude of treatment response. We performed a meta-analysis of subject data from 4 completed randomized amblyopia treatment trials,^2- 5 with similar entry criteria and similar timing of masked outcome assessment. The meta-analysis addressed whether magnitude of treatment response is influenced by the child's age, when treating with occlusion, atropine sulfate, 1%, or Bangerter filters.

A meta-analysis was conducted by pooling data from 996 children who were from 3 to less than 13 years of age who participated in 4 randomized multicenter clinical trials of treatment^2- 5 for amblyopia caused by strabismus, anisometropia, or both, conducted by the Pediatric Eye Disease Investigator Group (PEDIG).⁶ The protocols were registered at www.clinicaltrials.gov as NCT00315198, NCT00315302, NCT00315328, and NCT00525174 and were approved by the institutional review boards covering the participating centers. The protocols were (1) patching 2 hours per day with near or distance activities for children 3 to less than 7 years of age,³ (2) treatment with atropine with or without a plano lens for children 3 to less than 7 years of age,⁴ (3) treatment with atropine or patching 2 hours per day for children 7 to less than 13 years of age,² and (4) use of Bangerter filter or patching 2 hours per day for children 3 to less than 10 years of age.⁵ Complete protocols for all treatments are available on the PEDIG Web site (http://www.pedig.net) and summarized in Table 1.

These trials were specifically chosen because all 4 protocols required stability of amblyopic eye visual acuity in spectacles prior to enrollment, defined as at least 4 weeks of stable visual acuity or 16 weeks of spectacle wear. Therefore, any improvement in visual acuity would be primarily due to the additional treatment prescribed (patching, treatment with atropine with or without a plano lens, or use of Bangerter filter) rather than to spectacle correction. The 4 trials were not designed to determine the maximum treatment effect, and the primary outcome was assessed at 17 to 24 weeks following enrollment. Baseline characteristics of the cohort are summarized in Table 2.

Visual acuity at baseline was measured using either the Amblyopia Treatment Study visual acuity testing protocol using single-surrounded H, O, T, and V optotypes (hereafter referred to as the ATS HOTV protocol [Jaeb Center for Health Research, Tampa, Florida])⁷ for children from 3 to less than 7 years of age or the electronic Early Treatment Diabetic Retinopathy Study protocol using single-surrounded optotypes (hereafter referred to as the E-ETDRS protocol [Jaeb Center for Health Research])⁸ for children from 7 to less than 13 years of age, with each protocol using the Electronic Visual Acuity Tester.⁹ Baseline amblyopic eye visual acuities ranged from 20/40 to 20/400. Visual acuity at follow-up examinations was measured using the same testing method performed at baseline, regardless of age at follow-up. All visual acuity measures were converted to logMAR scores, and change in amblyopic eye visual acuity from enrollment was computed in logMAR lines.

A meta-analysis of individual subject data was performed using a multivariate linear regression model¹⁰ that evaluated the relationship between age group and improvement in amblyopic eye visual acuity (in logMAR lines of improvement), adjusting for factors that could be expected to influence outcome. Age was grouped into 3 categories (3 to <5 years, 5 to <7 years, and 7 to <13 years) because, in the initial analysis of these data, there was a nonlinear relationship between age and improvement in amblyopic eye visual acuity. It was not possible to fit a random effects model¹¹ for age owing to the small number of protocols and the partial overlap in age groups among the protocols; therefore, all factors, including age, were treated as fixed effects.

Covariate adjustments included the following: baseline amblyopic eye visual acuity, spherical equivalent refractive error in the amblyopic eye, prior amblyopia treatment (yes or no), type of amblyopia (anisometropic, strabismic, or combined anisometropic-strabismic), type of treatment (patching, treatment with atropine, or use of Bangerter filter), and protocol. Two-way interaction terms of the adjustment covariates with age group were also tested, and terms meeting a statistical significance criterion of P < .05 were retained in the model. Age-group comparisons of adjusted mean visual acuity improvement according to amblyopia severity were performed using the Tukey-Kramer multiple comparisons test¹² (2-sided α = .05).

The final multivariate linear regression model derived from the pooled data was applied separately to each protocol to confirm that pooled data estimates were consistent with estimates from the individual protocols. Possible heterogeneity among protocols in adjusted mean visual acuity improvement was tested by adding to the final meta-analysis model the interactions with protocol for all model terms that included age.¹³ Linear contrasts were used to identify the protocols that differed when protocol interactions indicated significant heterogeneity. All analyses were performed using SAS version 9.1 (SAS Institute, Cary, North Carolina).

Based on scatterplots of visual acuity change vs age by amblyopia severity at enrollment (Figure 1A and B), there appeared to be a decrease in treatment response with increasing age that was most evident for children with more severe amblyopia. The difference between severe and moderate amblyopia, in effect on treatment response, was confirmed by a highly significant interaction between age group and baseline amblyopic eye visual acuity (P < .001) in the meta-analysis.

In addition to an overall effect of age, we found an association between a greater improvement in amblyopic eye visual acuity and a less hyperopic amblyopic eye spherical equivalent (P = .002). There was a significant interaction between age group and prior amblyopia treatment (P = .02), indicating less improvement in amblyopic eye visual acuity with a history of prior amblyopia treatment (1.83 logMAR lines) than without (2.74 logMAR lines) in children 3 to less than 5 years of age (P = .02). There was no association of amblyopic visual acuity improvement with amblyopia type (P = .20), amblyopia study treatment (P = .14), and protocol (P = .28) (Table 3).

Adjusting for covariates in the regression model, children 7 to less than 13 years of age were significantly less responsive to treatment compared with younger subjects (3 to <5 years and 5 to <7 years) for both moderate amblyopia (P < .04 for all comparisons) and severe amblyopia (P < .001 for all comparisons) (Table 3). Treatment response did not differ statistically among children who were less than 7 years of age (3 to <5 years vs 5 to <7 years) for moderate amblyopia (P = .67) or severe amblyopia (P = .09), although the data suggested a steeper decline in response with age among children with severe amblyopia (Table 3).

There was some heterogeneity among protocols in adjusted mean visual acuity improvement, but only for children 3 to less than 5 years of age within the severe baseline amblyopia strata (P = .002). Specifically, there was a significantly greater response to treatment with atropine (protocol 2)⁴ compared with patching (protocol 1) for children 3 to less than 5 years of age with severe amblyopia at baseline³ (Figure 2A and B). Otherwise, the overall adjusted mean visual acuity improvement for each age group in the meta-analysis was consistent with the individual estimates from each protocol.

In a meta-analysis of outcome data from 4 randomized clinical trials, mean visual acuity improved with amblyopia therapy throughout the age range of 3 to less than 13 years. Children who were 7 to less than 13 years of age had less improvement than children who were 3 to less than 7 years of age for both moderate and severe amblyopia. Although treatment response was not statistically different across the age range of 3 to less than 7 years for both moderate and severe amblyopia, there was a suggestion of a steeper decline in response with age for children with severe amblyopia at baseline.

Earlier PEDIG studies did not require stability of visual acuity prior to starting patching or atropine treatment, but we had reached similar conclusions regarding the effect of age on treatment response. For example, among children 3 to less than 7 years of age, we found no evidence of reduced response in older children compared with younger children when treating with patching¹⁴ or atropine¹⁵ for moderate amblyopia. In contrast, for severe amblyopia, we previously found that the youngest children (3 to <5 years of age) were somewhat more responsive to either 6-h/d patching or full-time patching than were older children (5 to <7 years of age).¹⁶ Retrospective studies by Fulton and Mayer¹⁷ and Flynn et al¹⁸ have also reported reduced response to amblyopia treatment in older children, but these studies were limited by lack of a standardized outcome assessment. Conversely, other studies^19- 20 have reported significant improvement in amblyopic eye visual acuity in children older than 7 years.

There are at least 2 possible reasons for reduced response to amblyopia treatment in older children. It is widely believed that there is declining plasticity of the central nervous system as children age, although recent data on the treatment of amblyopia¹ suggest that the plasticity of the nervous system remains throughout adolescence. Second, there may be poorer compliance when treating older children. Such compliance issues could be studied by using occlusion dose monitors,^21- 23 but these devices are not currently commercially available and were not used in our studies.

Despite the reduced treatment response in older children (ie, 7 to <13 years of age) compared with younger children, there was still an improvement in the mean visual acuity with treatment, and some individuals responded dramatically. This difference in individual response also was found in the PEDIG study of treatment of teenagers¹; some had a dramatic response to 2 to 6 h/d of prescribed patching, whereas others had little or no response. Stewart et al²⁴ used occlusion dose monitors in somewhat younger children (mean [SD] age, 5.6 [1.5] years), and they observed a wide range of visual acuity improvement to a given dose of patching. The disparity of visual acuity response among teenagers in an earlier PEDIG study¹ may have been due to variable compliance, but the issue of compliance cannot be resolved because actual wearing time was not measured. Nevertheless, it seems reasonable to offer treatment to even older teenagers (eg, through age 17 years) because we are currently unable to predict which patients will or will not respond.

Regarding treatment of amblyopia with optical correction alone,²⁵ we do not know whether the response is age-dependent because the study protocols included in the present meta-analysis required wearing of optical correction for at least 16 weeks or until stable visual acuity was demonstrated prior to randomization. Nevertheless, it is noteworthy that a previous study of teenagers¹ had shown that there was improvement in amblyopic visual acuity from optical correction alone.

The strength of our study is the application of meta-analysis to 4 randomized trials of individual subject data with similar entry criteria, the length of follow-up, and the use of a masked and standardized outcome assessment. However, there are several limitations to our analysis. Our ability to separate protocol effects from age effects is dependent on a single protocol (ie, protocol 4), which was the only protocol that had overlap in age with all other protocols (Table 1). Also, protocol 4 did not include any children with severe amblyopia. Thus, separating an age effect from a protocol effect in severe amblyopia required that we assume the same protocol effects that were seen in moderate amblyopia (Figure 2A and B) (assuming that the lesser improvement seen in children 7 to less than 13 years of age was due to age and not to protocol).

Additional limitations include using arbitrary age categories to model age effects and using different visual acuity testing methods for children who were less than 7 years of age⁷ than for those who were 7 year of age or older.⁸ We used age categories to model age effects because there was evidence that the age effect was nonlinear, but it is likely that this effect follows a nonlinear continuum that we were unable to identify owing to a lack of sufficient overlap in ages included in each protocol and owing to the coarser granularity of the change measurements in the younger children tested with the ATS HOTV protocol compared with the older children tested with the E-ETDRS protocol (Figure 1). Testing with ATS HOTV leads to slightly better visual acuity scores than does testing with E-ETDRS, particularly in amblyopic eyes^26- 27 (a mean of 0.08 and 0.07 logMAR lines, respectively), but we do not believe that this influenced our primary finding of less responsiveness in older children because visual acuity was measured using the same method at enrollment and at outcome examination, so the potential bias between methods is minimized when looking at change. It is also possible that if there was a learning or maturation effect, such an effect might be greater in younger children. Nevertheless, improvement in the sound eye visual acuity was similar for younger and older children treated with patching in our studies. For example, the mean sound eye visual acuity improvement was 1.5 letters (mean, 0.3 logMAR lines) in children 7 to less than 13 years of age² and 0.3 logMAR lines in children 3 to less than 7 years old.³ None of the protocols collected visual acuity data beyond the 17- to 24-week study outcome examination, and we have no data on duration of amblyopia prior to treatment. Finally, these data can only be generalized to children with amblyopia caused by strabismus, anisometropia, or both combined.

In conclusion, while there is improvement in visual acuity across all age ranges (from 3 to <13 years of age), children 7 to less than 13 years of age are least responsive to amblyopia treatment. Although treatment response is not statistically different across the age range of 3 to less than 7 years for both moderate and severe amblyopia, there is a suggestion of a steeper decline in response with age for children with severe amblyopia at baseline. Despite reduced mean treatment response in children 7 to less than 13 years of age, some children in this age group showed marked improvement with treatment.